Nonlinear Population Pharmacokinetics of Sirolimus in Patients With Advanced Cancer

K, Wu; Cohen, Ezra E.W.; House, Larry; Ramirez, Joel L.; Zhang, W; Ratain, Mark J.; Bies, Robert R.

doi:10.1038/psp.2012.18

Cited by 20 publications

(29 citation statements)

References 30 publications

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“…The calculated apparent first compartment clearance found in patient 3 of 0.139 L/h/kg falls within this range ( Table 3 ). The apparent volume of distribution for the first (`central`) compartment (0.9 L/kg) is in keeping with sirolimus`protein binding and distribution in blood cells [ 1 ] and was also in the range reported by Wu and colleagues in a population pharmacokinetics study (53.4 L) [ 19 ]. Although it is not possible to draw conclusions from a single case, the pharmacokinetics of sirolimus in overdose appear to be similar to what is seen in the therapeutic dose range.…”

Section: Discussionsupporting

confidence: 72%

Acute Sirolimus Overdose: A Multicenter Case Series

Ceschi

Heistermann²,

S³

et al. 2015

PLoS ONE

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BackgroundThere are few data relating to sirolimus overdose in the medical literature. Our objectives were to describe all cases of overdose with sirolimus reported to Swiss, German and Austrian Poisons Centres between 2002-2013.MethodsAn observational case-series analysis was performed to determine circumstances, magnitude, management and outcome of sirolimus overdose.ResultsFive cases of acute sirolimus overdose were reported – three in young children and two in adults. Four were accidental and one was with suicidal intent. Two patients developed symptoms probably related to sirolimus overdose: mild elevation of alkaline phosphatase, fever and gastroenteritis in a 2.5-year-old male who ingested 3 mg, and mild changes in total cholesterol in an 18-year-old female after ingestion of 103 mg. None of these events were life-threatening. Serial blood concentration measurements were performed starting 24 h after ingestion of 103 mg in a single case, and these followed a similar pharmacokinetic time-course to measurements taken after dosing in the therapeutic range.ConclusionsAcute sirolimus overdose occurred accidentally in the majority of cases. Even large overdoses appeared to be well-tolerated, however children might be at greater risk of developing complications. Further study of sirolimus overdose is needed.

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Section: Discussionsupporting

confidence: 72%

Acute Sirolimus Overdose: A Multicenter Case Series

Ceschi

Heistermann²,

S³

et al. 2015

PLoS ONE

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“…The resulting population model estimates for CL matured , TM 50 , and Hill coefficient after this normalization were 20.6 L/h/70kg, 60.1 weeks, and 2.84 (detailed data not shown), respectively, and were comparable to the population estimates summarized in Table 2. For adults, sirolimus CL estimates were reported to be a range of 9.98 to 19.5 L/h/70kg in kidney transplant patients, [26][27][28][29][30] advanced cancer patients, 31 and healthy volunteers. 32 Our CL matured values, which were allometrically size-normalized with a power of 0.67 and 0.75, were slightly higher than reported mean values in adult patients possible due to coadministration of cyclosporine in adults but were close to estimates reported in healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

Characterizing the Developmental Trajectory of Sirolimus Clearance in Neonates and Infants

Emoto

Fukuda

Mizuno

et al. 2016

CPT Pharmacom & Syst Pharma

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Sirolimus is increasingly being used in neonates and infants, but the mechanistic basis of age‐dependent changes in sirolimus disposition has not been fully addressed yet. In order to characterize the age‐dependent changes, serial sirolimus clearance (CL) estimates in individual young pediatric patients were collected and analyzed by population modeling analysis. In addition, sirolimus metabolite formation was also investigated to further substantiate the corresponding age‐dependent change in CYP3A activity. The increasing pattern over time of allometrically size‐normalized sirolimus CL estimates vs. age was well described by a sigmoidal Emax model. This age‐dependent increase was also observed within each individual patient over a 4‐year study period. CYP3A‐dependent sirolimus metabolite formation changed in a similar fashion. This study clearly demonstrates the rapid increase of sirolimus CL over time in neonates and infants, indicating the developmental change. This developmental pattern can be explained by a parallel increase in CYP3A metabolic activity.

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“…A two-compartment model with first-order elimination was superior to a one-compartment model to describe yimitasvir PK profile. For the tested absorption model including first-order absorption with or without a lag time, sequential zero-first order absorption ( Tong et al, 2018a ; Tong et al, 2018b ), transit absorption ( Jain et al, 2011 ; Hu et al, 2018 ) and saturable Michaelis-Menten absorption ( Wu et al, 2012 ), transit absorption model had the smallest AIC value and fitted the data best from the goodness-of-fit plots. Sequential zero-first order absorption model also performed well.…”

Section: Resultsmentioning

confidence: 99%

Population Pharmacokinetic Analysis of Yimitasvir in Chinese Healthy Volunteers and Patients With Chronic Hepatitis C Virus Infection

Guan

Tang

Zhang³

et al. 2021

Front. Pharmacol.

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Yimitasvir is a novel, oral hepatitis C virus (HCV) non-structural protein 5A inhibitor for the treatment of chronic HCV genotype 1 infection. The objective of this analysis was to develop a population pharmacokinetic model of yimitasvir in Chinese healthy volunteers and HCV infection patients. The model was performed using data from 219 subjects across six studies. Nonlinear mixed effects models were developed using Phoenix NLME software. The covariates were evaluated using a stepwise forward inclusion (p < 0.01) and then a backward exclusion procedure (p < 0.001). A two-compartment model with sequential zero-first order absorption and first-order elimination reasonably described yimitasvir pharmacokinetics (PK). The apparent oral clearance and central volume of distribution were 13.8 l·h−1 and 188 l, respectively. The bioavailability (F) of yimitasvir decreased 12.9% for each 100 mg dose increase. Food was found to affect absorption rate (Ka) and F. High-fat meal decreased Ka and F by 90.9% and 38.5%, respectively. Gender and alanine aminotransferase were identified as significant covariates on apparent oral clearance. Female subjects had lower clearance than male subjects. Zero-order absorption duration was longer in healthy volunteers (2.17 h) than that in patients (1.43 h). The population pharmacokinetic model described yimitasvir PK profile well. Food decreased Ka and F significantly, so it was recommended to take yimitasvir at least 2 h before or after a meal. Other significant covariates were not clinically important.

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Nonlinear Population Pharmacokinetics of Sirolimus in Patients With Advanced Cancer

Cited by 20 publications

References 30 publications

Acute Sirolimus Overdose: A Multicenter Case Series

Acute Sirolimus Overdose: A Multicenter Case Series

Characterizing the Developmental Trajectory of Sirolimus Clearance in Neonates and Infants

Population Pharmacokinetic Analysis of Yimitasvir in Chinese Healthy Volunteers and Patients With Chronic Hepatitis C Virus Infection

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